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White matter protection by inhibitors of glial scar formation in perinatal hypoxia ischemia

围产期缺氧缺血时胶质疤痕形成抑制剂对白质的保护作用

基本信息

批准号：
10404658
负责人：
Stephen Arthur Back
金额：
$ 36.19万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10404658
关键词：
Adult Animal Model Astrocytes Attention Attenuated Blocking Antibodies Brain Brain Hypoxia-Ischemia Cerebral Palsy Cerebrum Childhood Chronic Cicatrix Clinical Trials Cognitive Diagnosis Diffuse Disease Enzymes Event Extracellular Matrix Failure Future Generations Genes Human Hyaluronic Acid Hyaluronidase Hypoxia In Vitro Learning Lesion Life Mediating Memory Modeling Molecular Motor Natural regeneration Neonatal Pathway interactions Perinatal Hypoxia Phase Premature Birth Protein Subunits Proteins Reaction Risk Rodent Role Signal Transduction Socialization Survivors TNF gene Testing Therapeutic Time Vertebral column astrocyte progenitor astrogliosis central nervous system injury connectome disability in vivo inhibiting antibody inhibitor insight inter-alpha-inhibitor kinase inhibitor myelination nervous system disorder neurobehavioral neuropsychiatric disorder novel novel strategies novel therapeutic intervention novel therapeutics oligodendrocyte progenitor preterm newborn prevent progenitor protein complex repaired response src-Family Kinases white matter white matter injury

项目摘要

Project Summary Survivors of preterm birth are commonly diagnosed with persistent white matter injury (WMI) that leads to a failure of normal myelination. Myelination failure results in life long motor and neurobehavioral disabilities. The central feature of WMI is the so-called “glial scar,” an inhibitory barrier generated by reactive astrocytes, which causes myelination failure by blocking the maturation of oligodendrocyte progenitors. It is our long-term objective to develop novel therapies to prevent myelination failure by preventing glial scar formation. There are no therapeutic strategies to prevent early formation of diffuse reactive astrogliosis before it chronically blocks myelination. WMI disrupts the integrity of the hyaluronic acid (HA) backbone of the extracellular matrix. We have defined a novel pathway through which small ~5 kDa HA oligomers (HA5) regulate the proliferation of astroglial progenitors and promote reactive astrogliosis. Through the enzyme tumor necrosis factor- (TNF) stimulated gene-6 (TSG-6), HA5 serves as a sink that traps heavy chain (HC) protein subunits of the inter-alpha-inhibitor protein (II) complex. This reaction generates unstable intermediates of II that release HC. We have identified novel approaches to block this TSG-6-dependent pathway to markedly attenuate the formation of the glial scar. Our over-riding hypothesis is that HA5-mediated HC release promotes reactive astrogliosis via a src family kinase-dependent pathway. We propose three specific aims to test this hypothesis. In aim 1, we hypothesize that hyaluronidase activation in the glial scar promotes the formation of HA5. We will determine the hyaluronidases (HYAL) that generate HA5 to promote formation of the glial scar and determine if a broad spectrum HYAL inhibitor reduces astrogliosis in response to WMI. In aim 2, we will test the hypothesis that HA5 promotes astrocyte proliferation and reactive astrogliosis through TSG-6-dependent release of heavy chains derived from II. We will determine if astrocyte proliferation in WMI is dependent on TSG-6 expression that promotes astrogliosis in vitro and in vivo via an HC-dependent mechanism. In aim 3, we hypothesize that activation of TSG-6 mediates glial scar formation via activation of src family kinases. We will first determine if a TSG-6 blocking antibody inhibits proliferation of astrocyte progenitors in vivo. We will test a src kinase inhibitor, currently in clinical trials, as a novel strategy to block glial scar formation and promote myelination. At the conclusion of these studies, we expect to define new therapeutic strategies to intervene during early WMI to prevent formation of the glial scar and promote myelination. Given that reactive astrogliosis is a central feature of many forms of CNS injury, our findings may have potential benefit for other pediatric and adult neurological disorders with prominent WMI.

项目总结